Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
  • C07H11/04—Phosphates; Phosphites; Polyphosphates
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
  • A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
  • A01N25/04—Dispersions, emulsions, suspoemulsions, suspension concentrates or gels
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS OR COOKING OILS
  • A23D9/00—Other edible oils or fats, e.g. shortenings or cooking oils
  • A23D9/007—Other edible oils or fats, e.g. shortenings or cooking oils characterised by ingredients other than fatty acid triglycerides
  • A23D9/013—Other fatty acid esters, e.g. phosphatides
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23J—PROTEIN COMPOSITIONS FOR FOODSTUFFS; WORKING-UP PROTEINS FOR FOODSTUFFS; PHOSPHATIDE COMPOSITIONS FOR FOODSTUFFS
  • A23J7/00—Phosphatide compositions for foodstuffs, e.g. lecithin
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
  • A23L29/10—Foods or foodstuffs containing additives; Preparation or treatment thereof containing emulsifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/55—Phosphorus compounds
  • A61K8/553—Phospholipids, e.g. lecithin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/67—Vitamins
  • A61K8/673—Vitamin B group
  • A61K8/675—Vitamin B3 or vitamin B3 active, e.g. nicotinamide, nicotinic acid, nicotinyl aldehyde
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/67—Vitamins
  • A61K8/676—Ascorbic acid, i.e. vitamin C
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/67—Vitamins
  • A61K8/678—Tocopherol, i.e. vitamin E
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • C—CHEMISTRY; METALLURGY
  • C05—FERTILISERS; MANUFACTURE THEREOF
  • C05F—ORGANIC FERTILISERS NOT COVERED BY SUBCLASSES C05B, C05C, e.g. FERTILISERS FROM WASTE OR REFUSE
  • C05F11/00—Other organic fertilisers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/06—Phosphorus compounds without P—C bonds
  • C07F9/08—Esters of oxyacids of phosphorus
  • C07F9/09—Esters of phosphoric acids
  • C07F9/10—Phosphatides, e.g. lecithin
  • C07F9/103—Extraction or purification by physical or chemical treatment of natural phosphatides; Preparation of compositions containing phosphatides of unknown structure
• • C—CHEMISTRY; METALLURGY
  • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
  • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
  • C09K23/00—Use of substances as emulsifying, wetting, dispersing, or foam-producing agents
  • C09K23/14—Derivatives of phosphoric acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
  • A61K2800/42—Colour properties
  • A61K2800/43—Pigments; Dyes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
  • A61K2800/52—Stabilizers

Definitions

• the subject of this invention are homogeneous formulations containing glycerophospholipids and polar or lipophilic substances, and a method of producing a these formulations.
• Glycerophospholipids play an important physiological role as building blocks for membranes, especially during compartmentation in biological systems. They are accordingly ubiquitous in animal, plant and microbial forms of life.
• natural glycerophospholipids consist of glycerol which is esterified in the C 1 and C 2 positions with fatty acids and carries a phosphatide ester in the C 3 position. From the point of view of quantity, by far the most important natural glycerophospholipids are the phosphatidyl derivatives phosphatidyl choline, phosphatidyl serine, phosphatidyl ethanolamine, phosphatidyl inositol and phosphatidic acid. In certain cell systems, however, there are, in addition, high concentrations of other phospholipids, eg, plasmalogens, cardiolipins or sphingomyelins.
• glycerophospholipids in vitro by means of chemical and/or enzymatic processes.
• the structure of the products obtained can correspond to that of natural glycerophospholipids, but can also be “synthetic”.
• biological sources still take precedence in industrial-scale production because they are readily available. This applies especially to plant lecithins, eg, from soybeans, rape or sunflower seed. These lecithins are obtained as a mixture of various phospholipid classes, so-called “raw lecithin”, in the refining process during the production of cooking oils.
• the most important animal source of glycerophospholipids is the yolk from hens' eggs, which is characterized by a high phosphatidyl choline content.
• phosphatidyl choline is particularly important.
• Naturally occurring glycerophospholipids can be modified such that their surface-active properties, in particular, are changed.
• glycerophospholipids are used technologically because of their emulsifying effect, which is exploited specifically to stabilise emulsions or suspensions, eg, traditionally in the food-processing sector, in industry, and in the pharmaceuticals sector.
• glycerophospholipids can also be used physiologically, because in vivo they fulfil important functions, especially as building blocks for membranes in biological cells.
• natural glycerophospholipids in particular, especially phosphatidyl cholines and cephalins are used for products or formulations which can be supplied directly or indirectly to humans.
• the resorption, pharmacokinetics and/or the pharmacological effect of active ingredients used in drugs can be varied by formulating them with glycerophospholipids.
• micro-crystalline system formulation by means of incorporating fine (micro-crystalline) particles of the solid polar or lipophilic substance in glycerophospholipids (“micro-crystalline system”)
• the polar substances are dissolved in polar solvents, usually water, and are surrounded by a single- or multi-layer membrane, eg, a bilayer membrane, consisting of surface-active glycerophospholipids.
• polar solvents usually water
• a single- or multi-layer membrane eg, a bilayer membrane, consisting of surface-active glycerophospholipids.
• the lipophilic substances in liquid form or dissolved in suitable solvents, are encapusulated in a similar way.
• a recent survey on this formulation technique is contained in H. Hauser, Phospholipid Vesicles in Cevc. G. (ed.), Phospholipid Handbook, Marcel Dekker, New York, 1993, pp. 603-637.
• micellar bilayer membrane for the formulation of polar substances in water or of lipophilic substances is, however, not unproblematic, and certain esters of phosphoric acid, eg, in the form of glycerophospholipids such as phosphatidyl choline, may have to be present in the membranes in order to impart the required stability.
• the inclusion rates for the active ingredients to be formulated are often low, so that large active-ingredient losses have to be allowed for during production of the formulation.
• sterol derivatives such as cholesterol are often needed to stabilise the membrane.
• Attempts have also been made to stabilise the membrane by forming an adduct—by means of a chemical bond—between cholesterol and the substance to be formulated (eg, J. L. Murtha et al., J. Pharm. Sci 83 (9), 1222-8, 1994).
• Another approach has been to produce liposomal formulations using supercritical carbon dioxide, rendering the use of large volumes of organic solvent unnecessary (Frederiksen L. et al, J. Pharmaceutical. Sci. 86, 921-8, 1997).
• Formulations of active ingredients have resulted in great progress, eg, in many therapies used in modern medicine; however, there are two main disadvantages, eg, in parenteral applications: for one, liposomes—as artificial micelles—have only a limited lifetime in vivo because lipid exchange reactions, in particular, can take place at membranes and thus destabilise the membranous vesicle or liposome, or even cause it to disintegrate, before it reaches the actual place of intended therapy. For another, especially in the case of larger micelles, the mononuclear phagocyte system becomes active, and leads to undesired immunological side reactions. For physical reasons, it is impossible to reduce the size of vesicular liposomes arbitrarily and thus to avoid the immune response, because the surface of the membrane, depending on its composition, will tear open as from a certain micelle size.
• the liquid components contained in the formulation are separated completely from the preparation by means of a spray tower and one- or multi-component nozzles, and the preparation is obtained in powder form.
• the disadvantages of this “spray-embedding” process are, on the one hand, the technical complexity:
• Formulations in which a substance of polar or lipophilic character is bound chemically to surface-active glycerophospholipids (“chemical-bond system”), of the type described, eg, by Hong et al. in Cancer Res. 50 (14), 4401-6 (1990), have the major disadvantage that this method is complicated and not generally applicable, an added problem being the fact that on account of the chemical bond, the substance's mode of action usually changes. Accordingly, this formulation strategy is limited in practice to just a few exceptional cases.
• the object of this invention was thus to provide homogeneous, anhydrous formulations comprising active ingredients, carriers, and maybe formulation aids, which do not have the described disadvantages of hitherto known formulations and which, in particular, reduce or completely prevent the formation of micro-crystalline particles.
• (C) maybe one or more formulation aids with at least two hydroxyl groups, characterized in that the glycerophospholipid component (A) and the component (B) are present in a molar ratio of 1:0.001 to 2 and—in cases where (C) is present—the glycerophospholipid component (A) and the component (C) are present in a molar ratio of 1:0.001 to 1.
• glycerophospholipids are understood to be compounds containing a glycerol radical which is esterified with at least one fatty acid radical and with at least one phosphatide radical.
• suitable classes of glycerophospholipids include phosphatidic acids, phosphatidyl esters, lyso-phospholipids, cardiolipins and plasmalogens. Preference is given to phosphatidyl esters and lyso-phospholipids which are esterified with a fatty acid radical at the C 1 atom of the glycerol, and with a phosphatide radical at the C 3 atom of the glycerol. It is especially beneficial to select the glycerophospholipids (A) from compounds which have the general formula (I):
• R 1 and R 2 can be the same or different, and each stand for a fatty acid radical with the general formula (II):
• R stands for straight-chain or branched-chain, saturated or mono- or polyunsaturated C 6 to C 24 fatty acid radicals, which may be substituted in the chain with, eg, OH or heteroatoms such as O, N or S, where R 2 can also be H, and where X is a radical from the series —H, CH 2 —CH 2 —NH 3 + , —CH 2 —CH 2 —N—(CH 3 ) 3 + , —CH 2 —CH(NH 3 + )COO ⁇ , —CH 2 —CH(—OH)—CH 2 —OH or
• the average molecular weights of the glycerophospholipids can be used as a basis for calculating the molar ratios.
• the formulations of the invention show a high level of stability and either do not dissociate into the starting components, or do so only to a minor extent.
• the formulations of the invention show solution behaviour which can be controlled selectively by way of the molar ratio of glycerophospholipid (A) to the polar or lipophilic substance (B): with an equimolar ratio of glycerophospholipid to polar substance, one possibility provided for according to the invention, the formulations are amphiphilic, ie, in a two-phase system they have a surface-active effect.
• these formulations are more lipophilic, ie, they can be incorporated well in oil.
• Water-soluble colouring agents for example, which have been formulated with an excess of glycerophospholipid, form clear, coloured solutions in oil at temperatures >50° C.
• formulation-aid-containing formulations of non-polar active ingredients which, at temperatures >50° C., can be dispersed readily in water to form a stable emulsion; the formulation can be sterilised by means of a 0.2 ⁇ m filter without deaggregating.
• the solubility of the overall formulation in water is improved significantly.
• formulations which contain lecithins and/or cephalins as glycerophospholipid component (A).
• substances (B) with polar and/or lipophilic properties it is preferable according to the invention to use physiological active ingredients or colouring agents, the molecular weight of which should be ⁇ 1500 daltons, and, in particular, ⁇ 500 daltons.
• the substances (B) have an affinity with glycerophospholipids, this affinity not necessarily resulting in a covalent chemical reaction but—as is especially preferred in this case—being manifested in the formation of non-covalent interactions such as secondary valences, so-called hydrogen bonds, and/or lipophilic interactions.
• the system is stabilised, with formation of the homogeneous, anhydrous aggregates (“molecular self-assemblies”) which are typical of the formulations of the invention and, as far as their structure is concerned, compare best with “solid solutions”.
• physiological active ingredients are understood to be all compounds or classes of substances which have a regulating or controlling influence on metabolic processes. Especially when administered to mammals or humans, the effect is naturally dependent on the form in which the active ingredient is administered.
• polar substance or “lipophilic substance” accordingly covers all polar and also some water-soluble or lipophilic active ingredients in drugs which are suitable for topical and transdermal applications, or which can be administered through the mouth, parenterally or by way of inhalation and, in particular here, intravenously, intramuscularly, subcutaneously, intraperitoneally or intranasally.
• the term also includes active ingredients used in cosmetics, and, in addition, agrochemicals such as fertilisers, plant growth regulators, herbicides and insecticides, and also biocides of general nature.
• the water-soluble vitamins or fat-soluble vitamins such as those of the groups A, D, E and K, are quoted by way of example.
• An example of the water-soluble colouring agents is Ponceau 4 R (E 124), while the carotinoids are important examples of the lipophilic colouring agents.
• the formulations of the invention are anhydrous, ie, they preferably contain less than 5 wt. %, better still less than 3 wt. % and best of all less than 1 wt. % of water, expressed in terms of the overall weight of the formulation.
• the formulations of the invention are oil-free, preferably containing a maximum of 3 wt. % and, better still, a maximum of 2 wt. % of oil, ie, triglycerides, expressed in terms of the overall weight of the formulation. It is of particular advantage if the formulations of the invention are solid at room temperature, eg, in the form of a free-flowing powder.
• the formulations may also contain one or more polyol compounds as formulations aids (C), the polyols pereferably being liquid polyols, especially C 2 -C 4 compounds, and containing at least two hydroxyl groups.
• formulations aids C
• the polyols in question can also be used in the form of arbitrary mixtures. It is of advantage, however, if the formulation aids for preparing the formulation are anhydrous, ie, preferably having a maximum water content of 5 wt. %, expressed in terms of the weight of the formulation aid.
• this invention includes a method of producing them, which is carried out in three main steps:
• substance (B) is provided in liquid form, eg, as a pure substance, assuming it is liquid under the conditions in question. It is preferable, however, if substance (B) is dissolved in an anhydrous solvent (mixture), ie, a solvent which preferably contains a maximum of 5 wt. % water. Polar and/or non-polar solvent (mixtures) are especially suitable for this purpose. It is also possible to admix the formulation aid (C), which again is anhydrous, with the solvent (mixture) in the molar ratios given. If a polar substance is to be formulated, this substance can also be dissolved exclusively in the anhydrous formulation aid.
• anhydrous solvent ie, a solvent which preferably contains a maximum of 5 wt. % water.
• Polar and/or non-polar solvent (mixtures) are especially suitable for this purpose. It is also possible to admix the formulation aid (C), which again is anhydrous, with the solvent (mixture) in the molar ratios given. If
• the polar solvents provided for in the invention are solvents of protic and/or aprotic character.
• protic solvents primary monovalent C 1-10 alcohols, secondary monovalent C 3 ⁇ 10 alcohols and tertiary monovalent C 4-10 alcohols, as well as arbitrary mixtures thereof, have proved to be especially suitable.
• aprotic solvents are halogenated C 1-10 hydrocarbons, especially chloroform, as well as ethers such as diethyl ether and tetrahydrofuran (THF), and also arbitrary mixtures thereof.
• Suitable non-polar solvents are aliphatic or cyclic C 5-10 hydrocarbons, and/or triglycerides.
• step (a) it is useful in step (a) to use mixtures of polar and non-polar solvent (mixtures) in a weight ratio of max. 1:1.
• step (b) The liquid or solution resulting from step (a) is then combined in step (b) with a glycerophospholipid (mixture) (A) in such a way that the dissolved state of the components is maintained.
• a glycerophospholipid component (A) is also used in the dissolved state, for which purpose, once again, anhydrous polar—but also non-polar—solvents or mixtures thereof are especially suitable.
• a formulation aid (C) may be present.
• aliphatic or cyclic C 5-10 hydrocarbons preferably hexane and/or cyclohexane, and/or triglycerides, have proved suitable in steps (a) and/or (b), as was mentioned before. From the group of triglycerides, preference is given in the invention especially to natural vegetable oils.
• the mixture of dissolved substances resulting from step (b) is subsequently subjected to an extraction process in order to remove the solvent (mixture).
• an extracting agent containing hydrocarbons such as propane and/or butane, which are gaseous under normal conditions.
• the extraction is carried out in a rectifying column under a pressure between 1 and 50 MPa and at a temperature from 20 to 150° C., using an extracting agent containing propane and/or butane; the extraction is conducted in such a manner that the extraction mixture is distributed between a homogeneous lower phase comprising glycerophospholipid (mixture) (A), substance (B) and maybe formulation aid (C), and an upper phase containing the solvent and maybe the substance (B), and that the lower phase separates from the upper phase, with the formulation being obtained from the lower phase, which is generally in the form of a melt.
• the method of the invention for producing the formulation can thus be carried out with no significant loss of the substance to be formulated.
• the solution of starting materials obtained from steps (a) and (b) is extracted in a rectifying column by an extracting agent (mixture) coming from the bottom and preferably consisting of propane with up to 95 wt. % dimethyl ether (DME).
• an extracting agent mixture coming from the bottom and preferably consisting of propane with up to 95 wt. % dimethyl ether (DME).
• the extraction conditions preferred according to the invention are a pressure between 1 and 50 MPa and a temperature of 20 to 150° C., with pressures in the range between 3 and 20 MPa and temperatures of 30 to 100° C. having proved especially suitable.
• the extracting agent (mixture) is conducted away, while the glycerophospholipid fraction, sinking in the form of a melt to the bottom of the column, takes up the substance (B) to be formulated, and also the formulation aid, if one was used; it is at this stage that the formulation containing the glycerophospholipid (mixture), the polar or lipophilic substance and, if one was used, the formulation aid, is actually formed, and this can take place entirely in the dissolved state.
• the temperature at the top being 5 to 50° C. higher than that at the bottom.
• the fused formulation at the bottom of the column which usually contains between 20 and 40 wt. % of extracting agent (mixture) can be discharged via a suitable arrangement of nozzles into an ambient-pressure environment and thus freed of extracting agent (mixture) by means of the resulting pressure reduction and/or an increase in temperature.
• the solvent (mixture) obtained as top product is likewise freed of extracting agent (mixture), again by means of a pressure reduction and/or an increase in temperature.
• a separator it is expedient to use a separator.
• the fused glycerophospholipid (mixture) (A) can take up the substance (B), which is to be formulated, directly from the solvent (mixture) of the feed mixture.
• the method of the invention serves to transform substances of polar and/or lipophilic character into homogeneous formulations with lipophilic or amphiphilic properties, so that they can be used for applications which up till now were very difficult or completely impracticable.
• these homogeneous formulations are especially suitable for the preparation of dispersions, emulsions and/or suspensions for the food processing industry, biotechnology, the agrochemicals, cosmetics and pharmaceuticals industries—here in particular for the formulation of active ingredients—but also for the paint and varnish industry and the leather industry.
• Additional subject matter of the invention is a pharmaceutical preparation containing a formulation according to the invention, maybe together with carriers, aids, fillers and/or diluents such as are common in the pharmaceuticals industry.
• the oil-free formulation formed according to the method of the invention (oil content less than 2 wt. %) was discharged at the bottom of the extraction column into an ambient-pressure environment by way of an arrangement of nozzles. Due to spontaneous evaporation of the propane, the formulation cooled and a free-flowing powder was obtained.
• the proportion of nicotinamide in the homogeneous formulation was 1.7 wt. %, which corresponds to a molar ratio of 0.1 (calculated on the basis of an average molecular weight of 700 daltons for the glycerophospholipids).
• 16 g nicotinamide (polar substance) were dissolved completely in a mixture of 30 g ethanol (99.8 %) and 21 g glycerol (anhydrous formulation aid) at 45° C., added to 500 g of a mixture of 65 wt. % glycerophospholipids (natural mixture from soybeans) and 35 wt. % triglycerides (soybean oil), and mixed carefully by stirring, likewise at 45° C.
• the mixture of dissolved substances was supplied by means of a high-pressure pump to an extraction column, approximately in the middle.
• the rectifying section of the column has about 5, and the stripping section about 7 theoretical stages. Compressed propane under a pressure of 50 bar served as extracting agent.
• the temperature was about 70° C., at the top of the column 80° C. and at the bottom of the column 60 C.
• the ratio of the mixture supplied (feed) to the extracting agent (propane) was on average 3 wt. %.
• the empty-pipe speed of the extracting agent in the column was 2 mm/s.
• the oil-free formulation formed according to the method of the invention (oil content less than 2 wt. %) was discharged at the bottom of the extraction column into an ambient-pressure environment by way of an arrangement of nozzles. Due to spontaneous evaporation of the propane, the formulation cooled and a free-flowing powder was obtained.
• the proportion of nicotinamide in the formulation was 4.4 wt. %, which corresponds to a molar ratio of 0.28, expressed in terms of the glycerophospholipid; the proportion of 5.8 wt.
• % glycerol in the formulation corresponds to a molar ratio of 0.5, expressed in terms of the glycerophospholipid (calculated on the basis of an average molecular weight of 700 daltons for the glycerophospholipids).
• nicotinamide (polar substance) were dissolved completely in 15 g glycerol (anhydrous formulation aid) at 45° C., added to 540 g of a mixture consisting of 60 wt. % glycerophospholipids (natural mixture from soybeans) and 40 wt. % triglycerides (soybean oil), and mixed carefully by stirring, likewise at 45 C.
• the mixture of dissolved substances was supplied by means of a high-pressure pump to an extraction column, approximately in the middle.
• the rectifying section of the column has about 5, and the stripping section about 7 theoretical stages.
• a compressed mixture of propane and about 25 wt. % butane under a pressure of 60 bar served as extracting agent.
• the temperature was about 75° C., at the top of the column 85° C. and at the bottom of the column 65° C.
• the ratio of the mixture supplied (feed) to the extracting agent was on average 5 wt. %.
• the empty-pipe speed of the extracting agent in the column was 2 mm/s.
• the oil-free formulation formed according to the method of the invention (oil content less than 2 wt. %) was discharged at the bottom of the extraction column into an ambient-pressure environment by way of an arrangement of nozzles. Due to spontaneous evaporation of the extracting agent mixture, the formulation cooled and a free-flowing powder was obtained.
• the proportion of nicotinamide in the formulation was 0.3 wt.
• % which corresponds to a molar ratio of 0.02, expressed in terms of the glycerophospholipid; the proportion of glycerol in the formulation was 4.4 wt. %, which corresponds to a molar ratio of 0.35, expressed in terms of the glycerophospholipid (calculated on the basis of an average molecular weight of 700 daltons for the glycerophospholipids).
• 38 g DL- ⁇ -tocopherol lipophilic substance
• a dissolved mixture consisting of 56 wt. % glycerophospholipids (natural mixture from soybeans), 30 wt. % triglycerides (soybean oil), 5 wt. % anhydrous glycerol (formulation aid) and 9 wt. % ethanol (99.8 %) and mixed carefully by stirring at 45 C.
• the mixture of dissolved substances was supplied by means of a high-pressure pump to an extraction column, approximately in the middle.
• the rectifying section of the column has about 6, and the stripping section about 6 theoretical stages. Compressed propane under a pressure of 40 bar served as extracting agent.
• the temperature was about 70° C., at the top of the column 75° C. and at the bottom of the column 65° C.
• the ratio of the mixture supplied (feed) to the extracting agent (propane) was on average 6 wt. %.
• the empty-pipe speed of the extracting agent in the column was 2 mm/s.
• the oil-free formulation formed (oil content less than 2 wt. %) was discharged at the bottom of the extraction column into an ambient-pressure environment by way of an arrangement of nozzles. Due to spontaneous evaporation of the propane, the formulation cooled and a free-flowing powder was obtained.
• the proportion of DL- ⁇ -tocopherol in the formulation was about 6 wt. %, which corresponds to a molar ratio of 0.1.
• the proportion of glycerol in the formulation was about 7 wt. %, which corresponds to a molar ratio of 0.6 (calculated on the basis of an average molecular weight of 700 daltons for the glycerophospholipids).
• the formulation thus obtained showed excellent dispersibility and stability in water.
• the temperature was about 75° C., at the top of the column 85° C. and at the bottom of the column 65° C.
• the ratio of the mixture supplied (feed) to the extracting agent (propane) was on average 5 wt. %.
• the empty-pipe speed of the extracting agent in the column was 2 mm/s.
• the oil-free formulation formed (oil content less than 2 wt. %) was discharged at the bottom of the extraction column into an ambient-pressure environment by way of an arrangement of nozzles. Due to spontaneous evaporation of the propane, the formulation cooled and a free-flowing red powder was obtained.
• the proportion of colouring agent in the formulation was about 0.08 wt. %, which corresponds to a molar ratio of about 0.001, while the proportion of glycerol in the formulation was about 3 wt. %, which corresponds to a molar ratio of about 0.23, in each case expressed in terms of the glycerophospholipid (calculated on the basis of an average molecular weight of 700 daltons for the phospholipids).
• the colouring agent formulation prepared in this way was stirred in a proportion of 2 %, at a temperature of 50° C., into refined soybean oil, producing a clear, red oil solution which was still stable after cooling to room temperature.
• the oil-free formulation formed (oil and ethanol content less than 2 wt. %) was discharged at the bottom of the extraction column into an ambient-pressure environment by way of an arrangement of nozzles. Due to spontaneous evaporation of the propane, the formulation cooled and a free-flowing powder was obtained.
• the proportion of glycolic acid in the formulation was about 8 wt. %, which corresponds to a molar ratio of about 0.8, (calculated on the basis of an average molecular weight of 700 daltons for the phospholipids).
• glycolic acid formulation obtained in this way was dissolved in 50 % n-hexane by way of gentle heating. A clear, stable solution was obtained.
• the temperature was about 75° C., at the top of the column 85° C. and at the bottom of the column 65° C.
• the ratio of the mixture supplied (feed) to the extracting agent (propane) was on average 5 wt. %.
• the empty-pipe speed of the extracting agent in the column was 2 mm/s.
• the oil-free formulation formed (oil and methanol content less than 2 wt. %) was discharged at the bottom of the extraction column into an ambient-pressure environment by way of an arrangement of nozzles. Due to spontaneous evaporation of the propane, the formulation cooled and a free-flowing powder was obtained.
• the proportion of ascorbic acid in the formulation was about 3.5 wt. % and the proportion of glycerol about 3 wt. %; this corresponds to a molar ratio of about 0.13 and 0.23 respectively (calculated on the basis of an average molecular weight of 700 daltons for the phospholipids).
• the formulation was dissolved in a proportion of 1 % in lard, and subjected to an accelerated oxidation test at 110° C. in a so-called rancimat. Compared with the blank reading (formulated matrix of lecithin and glycerol without ascorbic acid), the formulation showed significantly improved oxidative stability.
• ketoprofen were dissolved completely in a mixture of 10 g ethanol and 5 g anhydrous glycerol at 45° C., added to 156 g of a mixture consisting of 64 wt. % glycerophospholipids (natural mixture from soybeans) and 36 wt. % triglycerides (soybean oil), and mixed carefully by stirring at 60 C.
• the mixture of dissolved substances was supplied by means of a high-pressure pump to an extraction column, approximately in the middle.
• the rectifying section of the column had about 5, and the stripping section about 7 theoretical stages. Compressed propane under a pressure of 50 bar served as extracting agent.
• the temperature was about 75° C., at the top of the column 85° C. and at the bottom of the column 65° C.
• the ratio of the mixture supplied (feed) to the extracting agent (propane) was on average 4 wt. %.
• the empty-pipe speed of the extracting agent in the column was 2 mm/s.
• the oil-free formulation formed (oil and ethanol content less than 2 wt. %) was discharged at the bottom of the extraction column into an ambient-pressure environment by way of an arrangement of nozzles. Due to spontaneous evaporation of the propane, the formulation cooled and a free-flowing powder was obtained.
• the proportion of ketoprofen in the formulation was about 11 wt. % and the proportion of glycerol about 5 wt. %; this corresponds to a molar ratio of about 0.32 and 0.38 respectively (calculated on the basis of an average molecular weight of 700 daltons for the phospholipids).
• the powdery formulation showed excellent dispersibility in aqueous media.
• the temperature was about 75° C., at the top of the column 95 C and at the bottom of the column 55° C.
• the ratio of the mixture supplied (feed) to the extracting agent (propane) was on average 3 wt. %.
• the empty-pipe speed of the extracting agent in the column was 2 mm/s.
• the oil-free formulation formed (oil and ethanol content less than 2 wt. %) was discharged at the bottom of the extraction column into an ambient-pressure environment by way of an arrangement of nozzles. Due to spontaneous evaporation of the propane, the formulation cooled and a fine, free-flowing powder was obtained.
• the proportion of salicylic acid in the formulation was about 5 wt. %, which corresponds to a molar ratio of about 0.18 (calculated on the basis of an average molecular weight of 500 daltons for the hydrolysed phospholipids).
• the powdery formulation showed excellent dispersibility in aqueous media.

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• 1997
  • 1997-12-30 DE DE19758157A patent/DE19758157A1/de not_active Withdrawn
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